The Indus Valley Civilization (IVC) was among the earliest known urban cultures, thriving between 5,000 and 3,500 years ago along the Indus River and its tributaries in what is now Pakistan and northwest India. At its height from 4,500 to 3,900 years ago, the society was known for its planned cities, extensive infrastructure, and innovative water management systems. Despite this high level of development, the reasons behind its long, gradual downturn have remained difficult for researchers to fully explain.

Climate Simulations Reveal Temperature Rise and Reduced Rainfall

To investigate past conditions, Vimal Mishra and colleagues reconstructed climate patterns across the region spanning 5,000 to 3,000 years ago. Their analysis combined climate modeling with several indirect indicators of ancient environmental change. These included the chemical signatures preserved in stalactites and stalagmites from two Indian caves and water level histories recorded in five lakes across northwest India. Together, the data point to a temperature increase of about 0.5 degrees Celsius during this interval, along with a 10 to 20 percent reduction in annual rainfall.

The team also identified four extended drought periods occurring between 4,450 and 3,400 years ago. Each drought lasted more than 85 years and affected between 65 percent and 91 percent of the area associated with the IVC, indicating widespread and long-lasting impacts on water availability.

Shifts in Settlement Patterns During Prolonged Dry Periods

According to the authors, these droughts likely influenced where people chose to establish settlements. Between 5,000 and 4,500 years ago, most communities were situated in regions that received higher rainfall. After 4,500 years ago, settlement patterns changed, with populations moving closer to the Indus River. This shift may reflect increasing dependence on a more reliable water source as drought conditions intensified.

One particularly long drought lasting 113 years, identified between 3,531 and 3,418 years ago, aligns with archaeological evidence of widespread deurbanization in the region. Based on these findings, the researchers conclude that the Indus Valley Civilization did not collapse abruptly from a single climate event. Instead, the society likely experienced a prolonged and uneven decline in which repeated droughts became a significant contributing factor.

In many mammals, females are receptive to mating only when ovulating, which gives males a clear window to maximize reproductive success. Bonobos (Pan paniscus) differ from this pattern because females remain sexually receptive for long periods and develop a bright pink genital swelling that persists well beyond the actual fertile stage.

Tracking Wild Bonobos to Understand Fertility Signals

To examine how males respond to this unreliable signal, researchers observed a wild bonobo community at Wamba in the Luo Scientific Reserve in the Democratic Republic of the Congo. The team documented sexual interactions each day and visually assessed the degree of genital swelling in every female. They also collected urine samples on filter paper to measure estrogen and progesterone, allowing them to identify when ovulation occurred.

The data showed that the likelihood of ovulation was highest between 8 and 27 days after a female reached maximum swelling, a range that makes prediction challenging. Even so, male behavior closely followed the true timing of ovulation. Males focused their mating activity on females who had reached maximum swelling earlier and who had older infants, two indicators linked to a greater chance of ovulation.

Flexible Mating Strategies Maintain an Imperfect System

These findings reveal that males improve their reproductive success by combining information about swelling patterns with knowledge of a female’s reproductive history. Because males are able to estimate fertility reasonably well despite the lack of a precise signal, the researchers suggest there has been little evolutionary pressure to make the signal more accurate. This may help explain why the system has persisted over long evolutionary timescales.

The authors add, “In this study, we found that bonobo males, instead of trying to predict precise ovulation timing, use a flexible strategy — paying attention to the end-signal cue of the sexual swelling along with infant age — to fine-tune their mating efforts. This finding reveals that even imprecise signals can remain evolutionarily functional when animals use them flexibly rather than expecting perfect accuracy. Our results help explain how conspicuous but noisy ovulatory signals, like those of bonobos, can persist and shape mating strategies in complex social environments.”

Researchers Reflect on Months of Field Observation

“The male bonobos weren’t the only ones paying close attention to sexual swelling — we spent countless days in the rainforest at Wamba, DRC doing exactly the same thing! All that watching, sweating, and scribbling in our notebooks eventually paid off. By tracking these daily changes, we uncovered just how impressively bonobos can read meaning in a signal that seems noisy and confusing to us.”

This study was supported by the Global Environment Research Fund (D-1007 to TF) of the Japanese Ministry of the Environment, the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (22255007 to TF; and 25304019 to CH;), and the JSPS Asia-Africa Science Platform Program (2012-2014 to TF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dr. Nestler traces his interest in science back to an unusual home laboratory in the basement of his family’s house in Nassau County, Long Island. Guided by his father, a high school biology teacher in the New York City public school system, he learned how to design and carry out experiments. These projects later became award-winning science fair entries and set the stage for an academic path through Yale University, where he earned BA, PhD, and MD degrees while training under Dr. Greengard.

Building a New Field in Molecular Psychiatry

His decision to name his research group at Yale Medical School “The Laboratory of Molecular Psychiatry” turned out to be remarkably forward-thinking. At a time when applying molecular biology to psychiatric questions was still considered bold, Dr. Nestler and colleague Dr. Ron Duman recognized that the field was ready for a new scientific direction. The name reflected genuine ambition. Within a few years, he was appointed Founding Director of the Division of Molecular Psychiatry at Yale, a role made possible when the sitting Director, Dr. George Heninger, voluntarily stepped aside. Dr. Nestler often recalls this moment as an example of generosity that he has tried to extend to younger scientists throughout his career.

Breakthrough Insights Into Brain Adaptation

One of the most influential discoveries associated with his work involves the transcription factor ΔFosB. This protein accumulates in the brain’s reward circuits during prolonged drug exposure and sustained stress, altering patterns of gene expression in affected neurons. While most proteins break down quickly, ΔFosB remains active for weeks or months. This unusually long lifespan provides a biological explanation for how relatively brief experiences can produce long-lasting changes in mood, motivation, and behavior. Researchers around the world now view ΔFosB as a key contributor to vulnerability to addiction.

The interview highlights the type of forward-looking scientific dialogue that characterizes Genomic Press’s open-access publications, which make cutting-edge findings accessible to researchers globally. The organization’s commitment to broad, barrier-free dissemination has helped accelerate progress across multiple branches of medical science.

From Signaling Pathways to Single-Cell Biology

Over roughly forty years, the direction of this research has shifted in notable ways. Early work focused on intracellular signaling cascades, then expanded into the study of transcription factors and gene networks that shape behavior in specific parts of the brain. Approximately twenty years ago, Dr. Nestler’s team began exploring epigenetic regulation, the chromatin modifications that allow environmental conditions to produce lasting changes in brain function. Improvements in scientific tools have since enabled increasingly detailed studies: first at the level of whole brain regions, then individual cell types, and now single-cell analyses that reveal subtle differences unseen in earlier studies. These advances raise an important question: could these insights eventually lead to personalized treatments tailored to select neuron populations within a single patient?

Resilience as a New Direction in Mental Health Science

A defining aspect of this research program is the emphasis on resilience rather than solely on pathology. His laboratory identified specific molecular, cellular, and circuit-level signatures in animals that maintain normal behavior despite exposure to stress or drugs. These animals show natural protective features that are absent in more susceptible individuals. The idea that some brains possess built-in defenses has far-reaching implications, suggesting new ways to develop treatments that strengthen resilience instead of only repairing damage.

“In addition to seeking ways to reverse the deleterious effects of drug or stress exposure, it is possible to develop treatments that promote mechanisms of natural resilience in individuals who are inherently more susceptible,” Dr. Nestler explains in the interview. Several of these resilience-based approaches are now in clinical testing for depression, offering one of the clearest examples of basic research informing new therapeutic possibilities. The potential success of these treatments prompts important questions about how psychiatric care may evolve in the coming decade.

Cross-Species Evidence and the Need to Protect Scientific Integrity

Key discoveries from animal research have been supported by findings in postmortem human brain tissue from individuals with addiction and stress disorders, providing strong evidence that the principles uncovered in the laboratory translate to humans. Dr. Nestler’s publication record includes more than 800 papers and major textbooks on the neurobiology of mental illness and molecular neuropharmacology. His work has been cited more than 177,000 times, and his h-index of 210 places him among the most influential scientists worldwide.

When asked about his greatest concern for the future of science, he offers a clear warning: “My greatest fear is that science becomes politicized, whereas science must never be political. People in blue and red states get the same illnesses.” His message emphasizes the need to safeguard scientific independence at a time when political pressures threaten evidence-based research in many regions. The mission of Genomic Press to advance open-access medical science aligns strongly with this vision of science serving people everywhere.

A Life Shaped by Family, Mentorship, and Service

Outside of his research, Dr. Nestler values time spent with his wife Susan of 45 years, their three children David, Matt, and Jane, their spouses, and their five grandchildren, who range in age from eighteen months to four years. He describes his defining traits as hard work and generosity and considers organization and discipline to be his strongest skills. He also shares a desire to cultivate more patience and to become more willing to challenge unkind behavior.

When asked what brings him the most pride, he points not to the major honors he has received, including the Julius Axelrod Prize for Mentorship, the Gold Medal Award from the Society of Biological Psychiatry, election to the National Academy of Sciences and the National Academy of Medicine, and honorary doctorates from Uppsala University and Concordia University. Instead, he cites the achievements of his former students and postdoctoral fellows. Additional information about Dr. Nestler and other leaders in science can be found on the Genomic Press website: https://genomicpress.kglmeridian.com/.

His guiding philosophy comes from Theodore Roosevelt, who wrote that credit belongs to “the man who is actually in the arena, whose face is marred by dust and sweat and blood.” For nearly four decades, Dr. Nestler has remained in that arena, contributing discoveries that continue to shape how the world understands the brain and its response to adversity.

The study, published on December 10 in Aging, analyzed how much theobromine was present in participants’ blood and compared those levels with biological aging markers measured in blood samples.

What Biological Age Reveals

Biological age reflects how well a person’s body is functioning, rather than the number of years they have lived. This measure is based on DNA methylation, a collection of tiny chemical tags on DNA that shift as we grow older.

The research team examined data from two European groups, including 509 people from TwinsUK and 1,160 from KORA. Individuals with higher amounts of theobromine in their bloodstream tended to have a biological age that appeared younger than their chronological age.

Professor Jordana Bell, senior author and Professor in Epigenomics at King’s College London, said: “Our study finds links between a key component of dark chocolate and staying younger for longer. While we’re not saying that people should eat more dark chocolate, this research can help us understand how everyday foods may hold clues to healthier, longer lives.”

Theobromine Stands Out Among Cocoa Compounds

The team also investigated whether other cocoa or coffee metabolites showed similar patterns. Their results suggested that theobromine was the only compound with this specific association.

To estimate biological age, the researchers used two approaches. One method examined DNA changes that reflect the pace of aging. The second measured telomere length, which refers to protective structures at the ends of chromosomes. Telomeres naturally shorten with age and are linked to age-related health risks.

How Plant Molecules Influence Aging

Many plant compounds in foods can influence how genes operate by turning them on or off. These compounds, known as alkaloids, can interact with cellular systems that regulate gene activity and contribute to long-term health.

Theobromine is one such alkaloid. Although it is widely known for being toxic to dogs, it has been connected to possible benefits in humans, including a reduced risk of heart disease. Despite this, it has received relatively limited scientific attention until now.

Next Questions for Aging Research

Dr. Ramy Saad, lead researcher at King’s College London and also affiliated with University College London as a doctor in Clinical Genetics, said: “This is a very exciting finding, and the next important questions are what is behind this association and how can we explore the interactions between dietary metabolites and our epigenome further? This approach could lead us to important discoveries towards aging, and beyond, in common and rare diseases.”

The team, which includes Professor Ana Rodriguez-Mateos, a Professor of Human Nutrition at King’s College London, is now examining whether theobromine’s effect occurs on its own or if it works alongside other well-known components of dark chocolate such as polyphenols, which are recognized for their positive effects on health.

Why More Chocolate Is Not a Shortcut

Dr. Ricardo Costeira, a Postdoctoral Research Associate at King’s College London, said: “This study identifies another molecular mechanism through which naturally occurring compounds in cocoa may support health. While more research is needed, the findings from this study highlight the value of population-level analyses in aging and genetics.”

Although the findings are encouraging, the researchers caution that increasing dark chocolate consumption is not automatically beneficial. Chocolate also contains sugar, fat and other ingredients, and more work is needed to fully understand how theobromine interacts with the body and how it may influence aging.